GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway

Li, Jingjing; Wang, Qiujie; Yang, Yi; Lei, Chong; Yang, Fan; Liang, Li; Chang, Chen; Xia, Jie; Wang, Kai; Tang, Ni

doi:10.1186/s13046-019-1459-6

Cited by 41 publications

(42 citation statements)

References 46 publications

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“…[63] GSTZ1 expression is downregulated in tumor tissue compared to adjacent normal tissue and correlates with poor prognosis. [250] High GSTP1 expression correlates with better survival and smaller tumor size. [254] Lung cancer GPX3 expression is decreased in NSCLC tissues.…”

Section: Tumor Type Involvement Of the Gsh Systemmentioning

confidence: 99%

“…In that regard, GPX1, GPX3, and GPX7 expression were found to be decreased [ 144 , 240 , 241 , 242 , 243 ] in tumor tissues, while the expression of GPX2 and GPX4 was found to be upregulated [ 144 , 146 , 244 , 245 , 246 , 247 ]. In addition, GSTA1, GSTM1, and GSTZ1 are reported to be downregulated in tumor tissue and can correlate with a poor prognosis [ 63 , 248 , 249 , 250 , 251 ], while GSTT1, GSTO1, and GSTK1 are mostly reported to be upregulated in tumor tissue compared to the normal surrounding tissue [ 252 , 253 ]. The expression level of GSTP1 in tumor tissue is controversial [ 144 , 253 , 254 , 255 ], and its involvement in tumorigenesis could at least in part depend on its hypermethylation [ 256 , 257 , 258 , 259 , 260 ].…”

Section: Redox Homeostasismentioning

confidence: 99%

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The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

et al. 2020

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Cancer remains an elusive, highly complex disease and a global burden. Constant change by acquired mutations and metabolic reprogramming contribute to the high inter- and intratumor heterogeneity of malignant cells, their selective growth advantage, and their resistance to anticancer therapies. In the modern era of integrative biomedicine, realizing that a personalized approach could benefit therapy treatments and patients’ prognosis, we should focus on cancer-driving advantageous modifications. Namely, reactive oxygen species (ROS), known to act as regulators of cellular metabolism and growth, exhibit both negative and positive activities, as do antioxidants with potential anticancer effects. Such complexity of oxidative homeostasis is sometimes overseen in the case of studies evaluating the effects of potential anticancer antioxidants. While cancer cells often produce more ROS due to their increased growth-favoring demands, numerous conventional anticancer therapies exploit this feature to ensure selective cancer cell death triggered by excessive ROS levels, also causing serious side effects. The activation of the cellular NRF2 (nuclear factor erythroid 2 like 2) pathway and induction of cytoprotective genes accompanies an increase in ROS levels. A plethora of specific targets, including those involved in thioredoxin (TRX) and glutathione (GSH) systems, are activated by NRF2. In this paper, we briefly review preclinical research findings on the interrelated roles of the NRF2 pathway and TRX and GSH systems, with focus given to clinical findings and their relevance in carcinogenesis and anticancer treatments.

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Section: Tumor Type Involvement Of the Gsh Systemmentioning

confidence: 99%

Section: Redox Homeostasismentioning

confidence: 99%

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

et al. 2020

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“…It participates in the catabolism of phenylalanine/tyrosine and catalyzes the isomerization of maleylacetoacetate to fumarylacetoacetate 18 . We previously found that GSTZ1 was poorly expressed in HCC, and GSTZ1 deficiency could lead to metabolite succinylacetone accumulation and thereby activate the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway 19 , 20 . Considering the importance of GSTZ1 in the development and progression of HCC, GSTZ1 may be an anticancer hallmark for sorafenib resistance in HCC.…”

Section: Introductionmentioning

confidence: 99%

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

et al. 2021

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Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.

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“…Second, GSTZ1 (-/-) knockout mice demonstrated upregulation of NQO1 and activation of Nrf2-mediated antioxidant response pathways (Blackburn et al, 2006). Third, GSTZ1 knockout in hepatoma cells decreased glutathione concentrations, resulting in activation of Keap1/Nrf2 (Li et al, 2019). These studies show oxidative stress responses are activated following genetic ablation of GSTZ1.…”

Section: Discussionmentioning

confidence: 74%

Exposure of Rats to Multiple Oral Doses of Dichloroacetate Results in Upregulation of Hepatic Glutathione Transferases and NAD(P)H Dehydrogenase [Quinone] 1

et al. 2020

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Dichloroacetate is an investigational drug that is used in the treatment of various congenital and acquired disorders of energy metabolism. Although DCA is generally well-tolerated, some patients experience peripheral neuropathy, a side effect more common in adults than children. Repetitive DCA dosing causes downregulation of its metabolizing enzyme, GSTZ1, which is also critical in the detoxification of maleylacetoacetate and maleylacetone. GSTZ1 (-/-) knockout mice show upregulation of GSTs and antioxidant enzymes as well as an increase in GSSG:GSH, suggesting GSTZ1 deficiency causes oxidative stress. We hypothesized that DCA-mediated depletion of GSTZ1 causes oxidative stress and used the rat to examine induction of GSTs and antioxidant enzymes after repeated DCA exposure. We determined the expression of A, M, P, and O-class GSTs, NAD(P)H quinone dehydrogenase 1 (NQO1), gamma-glutamylcysteine ligase complex (GCLC), and glutathione synthetase (GSS). GSH and GSSG levels were measured by LC/MS/MS. Enzyme activity was measured in hepatic cytosol using 1-chloro-2,4dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), and 2,6-dichloroindophenol (DCPIP) as substrates. In comparison to acetate-treated controls, DCA dosing increased the relative expression of GSTA1/A2 irrespective of rodent age, whereas only adults displayed higher levels of GSTM1 and GSTO1. NQO1 expression and activity were higher in juveniles after DCA dosing. GSH concentrations were increased by DCA in adults but the GSH:GSSG ratio was not changed. Levels of GCLC and GSS were higher and lower, respectively, in adults treated with DCA. We conclude that DCA-mediated depletion of GSTZ1 causes oxidative stress and promotes the induction of antioxidant enzymes that may vary between age groups.

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GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway

Cited by 41 publications

References 46 publications

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

Exposure of Rats to Multiple Oral Doses of Dichloroacetate Results in Upregulation of Hepatic Glutathione Transferases and NAD(P)H Dehydrogenase [Quinone] 1

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